Ipratropium bromide (N-isopropyl-notropine-tropic acid ester methylbromide), also known as Sch 1000, is an atropine-like agent which has been developed as an aerosol bronchodilator drug. This compound is believed to produce bronchodilata-tion by inhibiting increases in levels of cyclic guano-sine monophosphate mediated by cholinergic receptors, as contrasted with the action of adrenergic receptor stimulants in raising levels of cyclic adenosine monophosphate. Previous investigations have shown effective bronchodilation by ipratropium in asthmatic patients. This study was undertaken to establish the efficacy of ipratropium in chronic bronchitis, to confirm the efficacy of the drug in asthma, to compare it with isoproterenol, and to determine the optimal dose.
Materials and Methods
Twenty patients of the Pulmonary Section of the Boston City Hospital were admitted to the study. Individuals with glaucoma, pregnancy, or significant cardiac, renal, hepatic, or metabolic diseases were excluded. All patients had at least partially reversible airway obstruction, as judged by at least a 20 percent improvement in their forced expiratory volume at one second (FEVi) within 90 minutes after inhaling 150^g of isoproterenol. In seven of the patients, the principal pulmonary diagnosis was chronic bronchitis. Ten patients were diagnosed as having chronic bronchial asthma. Many of these individuals had a history of allergy, eosinophilia of the peripheral blood or sputum (or both), and paroxysms of wheezing and dyspnea responsive to bronchodilator drugs (description of inhalers you can see here). Chronic asthmatic bronchitis, also referred to as intrinsic asthma, was diagnosed in three patients who had no previous history of allergy; their asthmatic symptoms usually developed in association with acute or chronic respiratory infection. For purposes of analysis, the patients with chronic bronchitis and chronic asthmatic bronchitis have been grouped together. No short-acting bronchodilator drugs or other sympathomimetic drugs were permitted for at least eight hours prior to testing, and no long-acting bronchodilator drugs or anti-histaminic drugs were permitted for 12 hours prior to testing. All anticholinergic drugs were excluded for at least 24 hours prior to the initial testing and for the duration of the study. Concomitant therapy with steroids was allowed if the subject’s condition was stabilized with a daily dose of no more than 10 mg of prednisone, or a comparable drug, and if the dose was not varied during the study. Other maintenance therapy was continued on a normal regimen in the intervals between days of testing.
All individuals received a total of seven treatments with an interval of at least 24 hours between each. Isoproterenol was administered in doses of 75ju,g and 150^g; ipratropium bromide was administered in doses of 10/zg, 20/ug, 40/g, and 80 g. These two bronchodilator drugs, as well as a placebo, were given in random order, except that the doses of ipratropium were given in increasing strengths. In order to exclude diurnal variations, all treatments were given in the early morning. On each day of study, a coded aerosol was administered only if the baseline FEV1 was within 10 percent of the qualifying baseline FEV1. Otherwise, a test dose was not given on that day. Spirometric studies (using the Air-Shields Pulmonary Function Recorder) were performed 5, 15, 30, 60, 120, 180, 240, 300, and 360 minutes after the dose was administered. From the best of the three tracings obtained at each interval, the forced vital capacity (FVC), FEVX and the mean forced expiratory flow between 200 and 1,200 ml of the FVC (FEF200_1200) were calculated. At the time of each spirometric test, the pulse and blood pressure were also recorded. A physical examination, as well as a complete blood cell count, urinalysis, and determinations of blood chemistry, were performed upon entering and concluding the study. Patients were encouraged to report any side effects.
Duncan’s new multiple range test was used to compare the mean changes from baseline after each dose of ipratropium and isoproterenol and after placebo at each of the times of measurement. The estimate of variance used in this test was derived from Winer’s two-way analysis of variance.